PROJECT 2: Characterizing Treatment Responses with PDX Models for Lung and Bladder Tumors PROJECT SUMMARY/ASTRACT Lung squamous cell carcinoma and urothelial carcinoma are among the ten most common cancers in the United States. After disease progression on first-line chemotherapy for advanced cancers, immunotherapy is commonly used with a response rate at approximately 20%, and other treatment options are very limited. The prognosis has not changed significantly over the last three decades. Significant cancer treatment disparities exist between Non-Hispanic White and African American patients with these two cancer types. Genetic aberrations relevant to several FDA approved drugs or compounds in clinical trials have been identified. The goal of this project is to develop effective molecularly targeted therapies, either as single agents or in combination, with the long-term goal of improving the cancer health care and reducing disparities of these two cancers. Through the collaboration with The Jackson Laboratory (JAX), we have established 28 lung squamous cell carcinoma and 23 advanced urothelial cancer patient-derived xenograft (PDXs). Deep sequencing revealed that these cancers harbor many ?druggable? alterations. We have performed extensive drug efficacy studies, supported by clinical data, showing that some of these genetic alterations can potentially serve as therapeutic targets to treat these two cancers. However, primary and secondary resistance develops. In this project, first, we will screen large numbers of patient-derived tumor cell cultures (organoids, re- programmed tumor cells) and PDXs for effective drugs or drug combinations. We then validate the efficacy of these treatments and determine the toxicity in mice carrying PDXs. We will also determine the mechanisms of resistance using our newly developed eyePOD PDXs together with signal transduction reporters in which PDXs are established in eyes to allow monitoring of pharmacodynamic effects of targeted therapy, tumor growth, angiogenesis, drug resistance and mechanisms of resistance live in vivo under physiological conditions in the same tumor over a period of several months without sacrificing the mice.